Theories regarding the pathophysiology of migraine have been dominated since 1938 by the work of Graham and Wolff. Arch. Neurol. Psychiatry, 39:737-63, 1938. They proposed that the cause of migraine headache was vasodilatation of extracranial vessels. This view was supported by knowledge that ergot alkaloids and sumatriptan, a hydrophilic 5-HT1 agonist which does not cross the blood-brain barrier, contract cephalic vascular smooth muscle and are effective in the treatment of migraine. Humphrey, et al., Ann. NY Acad. Sci., 600:587-600, 1990. Recent work by Moskowitz has shown, however, that the occurrence of migraine headaches is independent of changes in vessel diameter. Cephalalgia, 12:5-7, 1992.
Moskowitz has proposed that currently unknown triggers for pain stimulate trigeminal ganglia which innervate vasculature within the cephalic tissue, giving rise to release of vasoactive neuropeptides from axons on the vasculature. These released neuropeptides then activate a series of events, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan and ergot alkaloids by mechanisms involving 5-HT receptors, believed to be closely related to the 5-HT1D subtype, located on the trigeminovascular fibers. Neurology, 43(suppl. 3):S16-S20 1993.
Serotonin (5-HT) exhibits diverse physiological activity mediated by at least seven receptor classes, the most heterogeneous of which appears to be 5-HT1. A human gene which expresses one of these 5-HT1 receptor subtypes, named 5-HT1F, was isolated by Kao and coworkers. Proc. Natl. Acad. Sci. USA, 90:408-412, 1993. This 5-HT1F receptor exhibits a pharmacological profile distinct from any serotonergic receptor yet described. The high affinity of sumatriptan at this subtype, Ki=23 nM, suggests a role of the 5-HT1F receptor in migraine.
This invention relates to novel 5-HT1F against which inhibit peptide extravasation due to stimulation of the trigeminal ganglia, and are therefore useful for the treatment of migraine and associated disorders.
The present invention relates to a compound of formula I: 
or a pharmaceutical acid addition salt thereof; where:
A is nitrogen or carbon;
D is oxygen, sulfur, or NH;
E is carbon or nitrogen;
Gxe2x80x94J is CH2xe2x80x94CH or CHxe2x95x90C;
R is phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, or substituted heteroaryl;
R1 is hydrogen or C1-C6 alkyl;
R2 is hydrogen or C1-C6 alkyl;
R3 is hydrogen or R2 and R3 combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring; with the proviso that
1) A may be nitrogen only when D is NH and E is carbon;
2) E may be nitrogen only when D is NH and A is carbon;
3) when E is nitrogen, R1 is not a substituent; or a pharmaceutical acid addition salt thereof.
This invention also relates to a pharmaceutical formulation comprising a compound of formula I, or a pharmaceutical acid addition salt thereof, and a pharmaceutical carrier, diluent, or excipient.
In addition, the present invention relates to a method for activating 5-HT1F receptors in mammals comprising administering to a mammal in need of such activation an effective amount of a compound of formula I, or a pharmaceutical acid addition salt thereof.
Moreover, the current invention relates to a method for inhibiting neuronal protein extravasation comprising administering to a mammal in need of such inhibition an effective amount of a compound of formula I, or a pharmaceutical acid addition salt thereof.
One embodiment of this invention is a method for increasing activation of the 5-HT1F receptor for treating a variety of disorders which have been linked to decreased neurotransmission of serotonin in mammals. Included among these disorders are depression, migraine pain, bulimia, premenstrual syndrome or late luteal phase syndrome, alcoholism, tobacco abuse, panic disorder, anxiety, general pain, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism, trichotillomania, trigeminal neuralgia, dental pain or temperomandibular joint dysfunction pain. The compounds of this invention are also useful as a prophylactic treatment for migraine. Any of these methods employ a compound of formula I.
The use of a compound of formula I for the activation of the 5-HT1F receptor, for the inhibition of peptide extravasation in general or due to stimulation of the trigeminal ganglia specifically, and for the treatment of any of the disorders described above, are all embodiments of the present invention.
The general chemical terms used throughout have their usual meanings. For example, the term xe2x80x9c6:5, 6:6, or 6:7 fused bicyclic ringxe2x80x9d refers to moieties of the formula: 
respectively.
The compounds of formula I where R2 and R3 combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring (indolizinyl, quinolizinyl, or 1-azabicyclo[5.4.0]undecanyl ring respectively) contain a chiral center located in that bicyclic ring. This chiral center is located at the bridghead carbon ring system. Furthermore, when R2 and R3 combine and Gxe2x80x94J is CH2xe2x80x94CH, the CH group of Gxe2x80x94J is a chiral center as well. Such centers are designated xe2x80x9cRxe2x80x9d or xe2x80x9cSxe2x80x9d. For the purposes of the present application, the numbering system for naming the substituents around the 1H-indole, benzofuran, benzothiophene, indazole, and 4-aza-1H-indole rings and the R,R and S,S enantiomers are illustrated below where n is 0, 1, or 2 and A, D, E, R, and R1 are as defined above. 
All enantiomers (S,R; R,S; S,S; R,R), diastereomers, and mixtures thereof, are included within the scope of the present invention.
The term xe2x80x9cC1-C4 alkylxe2x80x9d includes such groups as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and cyclobutyl. The term xe2x80x9cC1-C6 alkylxe2x80x9d includes those groups listed for C1-C4 alkyl and also refers to saturated straight, branched, or cyclic hydrocarbon chains of 5 to 6 carbon atoms. Such groups include, but are not limited to, pentyl, pent-2-yl, pent-3-yl, neopentyl, cyclopentyl, hexyl, cyclohexyl, and the like.
The term xe2x80x9chaloxe2x80x9d includes fluoro, chloro, bromo and iodo.
The term xe2x80x9cC1-C6 alkoxyxe2x80x9d refers to a C1-C6 alkyl group bonded through an oxygen atom. The term xe2x80x9cC1-C4 alkoxyxe2x80x9d refers to a C1-C4 alkyl group bonded through an oxygen atom. The term xe2x80x9cC1-C4 alkylthioxe2x80x9d refers to a C1-C4 alkyl group bonded through a sulfur atom. The term xe2x80x9c(C1-C4 alkyl)sulfonylxe2x80x9d refers to a C1-C4 alkyl group bonded through a sulfonyl moiety. The term xe2x80x9cC1-C4 acylxe2x80x9d refers to a formyl group or a C1-C3 alkyl group bonded through a carbonyl moiety.
The terms xe2x80x9csubstituted phenylxe2x80x9d and xe2x80x9csubstituted naphthylxe2x80x9d refer to a phenyl and naphthyl moiety, respectively, substituted once with halo, C1-C4 alkyl, C1-C6 alkoxy, C1-C4 alkylthio, nitro, cyano, amino, (C1-C4 alkyl)2amino, NHxe2x80x94(C1-C4 acyl), NHC(O)-heteroaryl, NHC(O)-phenyl, NHC(O)-substituted phenyl, carboxamido, trifluoromethyl, trifluoromethoxy, phenyl, C1-C4 acyl, benzoyl or (C1-C4 alkyl)sulfonyl, or two to three substituents independently selected from: halo, nitro, C1-C4 alkyl, trifluoromethyl, and C1-C4 alkoxy.
The term xe2x80x9cheteroarylxe2x80x9d is taken to mean an aromatic 5- or 6-membered ring containing from 1 to 3 heteroatoms selected from: nitrogen, oxygen and sulfur, said ring optionally being benzofused. Aromatic rings include furyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like. Benzofused aromatic rings include isoquinolinyl, benzoxazolyl, benzthiazolyl, quinolinyl, benzofuranyl, benzothiophenyl, indolyl and the like.
The term xe2x80x9csubstituted heteroarylxe2x80x9d is taken to mean an aromatic or benzofused aromatic heterocycle as defined in the previous paragraph substituted with up to three substituents independently selected from: halo, C1-C4 alkoxy, C1-C4 alkyl, cyano, nitro, hydroxy, NHC(O)-heteroaryl, S(O)nxe2x80x94(C1-C4 alkyl) and S(O)n-phenyl where n is 0, 1, or 2.
The term xe2x80x9camino protecting groupxe2x80x9d as used in this specification refers to a substituents commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the trityl group, the triisopropyl silyl group, the phthalimido group, the acetyl group, the trichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (xe2x80x9cFMOCxe2x80x9d), and the like; and like amino protecting groups. The species of amino protecting group employed is not critical so long as the derivitized amino group is stable to the condition of subsequent reactions on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of groups referred to by the above terms are described by T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1991, Chapter 7 hereafter referred to as xe2x80x9cGreenexe2x80x9d.
The term xe2x80x9cpharmaceuticalxe2x80x9d when used herein as an adjective, means substantially non-toxic and substantially non-deleterious to the recipient.
By xe2x80x9cpharmaceutical formulationxe2x80x9d it is further meant that the carrier, solvent, excipients and salt must be compatible with the active ingredient of the formulation (a compound of formula I).
The term xe2x80x9cacid addition saltxe2x80x9d refers to a salt of a compound of formula I prepared by reaction of a compound of formula I with a mineral or organic acid. For exemplification of pharmaceutical acid addition salts see, e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D. C., J. Pharm. Sci., 66:1, 1977.
The term xe2x80x9ceffective amountxe2x80x9d means an amount of a compound of formula I which is capable of activating 5-HT1F receptors and/or inhibiting neuronal protein extravasation.
The term xe2x80x9csuitable solventxe2x80x9d refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.
The following group is illustrative of compounds contemplated within the scope of this invention:
5-phenyl-3-(1-methylpiperidin-4-yl)benzofuran;
5-(4-fluorophenyl)-3-(octahydroindolizin-7-yl)-2-methylbenzothiophene;
5-(2-chlorophenyl)-2-chloroethenyl)-3-(1-ethylpiperidin-4-yl)-2-ethyl-1H-indole;
5-(3-methoxyphenyl)-3-(octahydro-2H-quinolizin-2-yl)-1H-indazole;
5-(3,4,5-trifluorophenyl)-3-(1-propylpiperidin-4-yl)-2-propyl-4-aza-1H-indole;
5-(thien-2-yl)-3-(1-azabicyclo[5.4.0]undecan-4-yl)-2-cyclopropylbenzofuran;
5-(thien-3-yl)-3-(1-isopropylpiperidin-4-yl)-2-n-butylbenzothiophene;
5-(benzamidazol-2-yl)-3-(octahydroindolizin-7-yl)-2-s-butyl-1H-indole;
5-(naphth-1-yl)-3-(1-n-butylpiperidin-4-yl)1H-indazole;
5-(pyrazin-2-yl)-3-(octahydro-2H-quinolizin-2-yl)-2-t-butyl-4-aza-1H-indole;
5-(oxazol-2-yl)-3-(1-s-butylpiperidin-4-yl)-2-cyclobutylbenzofuran;
5-(quinolin-4-yl)-3-(1-azabicyclo[5.4.0]undecan-4-yl)benzothiophene;
5-(isothiazol-5-yl)-3-(1-t-butylpiperidin-4-yl)1H-indole;
5-(pyrimidin-2-yl)-3-(octahydroindolizin-7-yl)1H-indazole;
5-(isoxazol-4-yl)-3-(1-cyclopropylpiperidin-4-yl)4-aza-1H-indole;
5-(benzimidazol-2-yl)-3-(octahydro-2H-quinolizin-2-yl) benzofuran;
5-(5-fluorobenzimidazol-2-yl)-3-(1-cyclobutylpiperidin-4-yl)benzothiophene;
5-(5-methoxybenzimidazol-2-yl)-3-(1-azabicyclo[5.4.0]undecan-4-yl)1H-indole;
5-(naphth-2-yl)-3-(1-methylpiperidin-4-yl)1H-indazole;
5-(5-fluoronaphth-2-yl)-3-(octahydroindolizin-7-yl)4-aza-1H-indole;
5-(7-methoxynaphth-1-yl)-3-(1-methylpiperidin-4-yl)-2-methylbenzofuran;
5-(3-chloronaphth-1-yl)-3-(1,2,3,4,5,8-hexahydroindolizin-7-yl)-2-ethyl benzothiophene;
5-(4-trifluoromethylnaphth-2-yl)-3-(1-ethylpiperidin-4-yl)-2-propyl-1H-indole;
5-(3,5-difluoro-4-methoxyphenyl)-3-(1,4,5,6,7,8,9-heptahydroquinolizin-2-yl)-1H-indazole;
5-(2-carboxamidonaphth-1-yl)-3-(1-propylpiperidin-4-yl)-2-cyclopropyl-4-aza-1H-indole; and
5-(thiazol-2-yl)-3-(1-azabicyclo[5.4.0]undec-3-en-4-yl)-2-isopropylbenzofuran.
While all enantiomers, all diastereomers, and mixtures thereof are useful as 5-HT1F agonists, single enantiomers and single diastereomers are preferred. Furthermore, while all of the compounds of this invention are useful as 5-HT1F agonists, certain classes are preferred. The following paragraphs describe such preferred classes.
a) A is carbon;
b) A is nitrogen, D is NH, and E is carbon;
c) D is NH and E is carbon;
d) D is sulfur;
e) D is oxygen;
f) D is NH and E is nitrogen;
g) Gxe2x80x94J is CH2xe2x80x94CH;
h) Gxe2x80x94J is CHxe2x95x90C;
i) R1 is hydrogen;
j) R1 is C1-C4 alkyl;
k) R1 is methyl;
l) R2 is hydrogen or C1-C4 alkyl;
m) R2 is methyl;
n) R2 and R3 combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring;
o) R2 and R3 combine, together with the 6 membered ring to which they are attached, to form a 6:6 fused bicyclic ring;
p) when R2 and R3 combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring, the compound is the R,R or S,R isomer;
q) when R2 and R3 combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring, the compound is the S,S or R,S isomer;
r) the substitution patterns found in the compounds of the Examples section;
s) the compounds of the Examples section;
t) the compound is an acid addition salt;
u) the compound is the hydrochloride salt;
v) the compound is the oxalate salt; and
w) the compound is the fumarate salt.
It will be understood that the above classes may be combined to form additional preferred classes.
It is preferred that the mammal to be treated by the administration of compounds of this invention is human.
The compounds of formula I may be prepared via a catalytic biaryl cross-coupling reaction. For a review of these cross coupling reactions see, e.g., Stanforth, S. P., xe2x80x9cCatalytic Cross-coupling Reactions in Biaryl Synthesisxe2x80x9d, Tetrahedron, 54:263-303, 1998. Typically, compounds of formula I may be prepared from compounds of formula II and III as illustrated in Scheme 1 below where R4 and R5 are chloro, bromo, OSO2CF3, B(OH)2, or Sn(C1-C4 alkyl)3 provided that one of R4 and R5 must be selected from chloro, bromo, and OSO2CF3 and one of R4 or R5 must be selected from B(OH)2 and Sn(C1-C4 alkyl)3 and A, D, E, G, J, R2, and R3 are as defined above. 
Compounds of formula I may be prepared by various aryl-aryl coupling methods. One such method is the Suzuki coupling, i.e., the coupling of an aryl halide or triflate with an aryl boronic acid. For a review of the Suzuki coupling, see, e.g., Tetrahedron, 54:285-292, 1998. Such a coupling may be performed by dissolving or suspending an aryl boronic acid of formula II or III, an aryl chloride, bromide, or triflate of formula II or III, a catalytic amount of palladium(0), and a weak aqueous base in a suitable solvent such as tetrahydrofuran or toluene. Typical reaction temperatures range from ambient to the reflux temperature of the mixture. Preferably, the reaction is performed at the reflux temperature of the mixture. Typical reaction times range from 1 to about 48 hours but, generally, the reaction is substantially complete after about 18 hours.
Generally, the aryl boronic acid is employed in a molar excess relative to the aryl halide. Such excesses typically range from about 1.01 to about 1.6 equivalents. Suitable sources of palladium(0) include, but are not limited to, palladium(0) bis(dibenzylidineacetone), tetrakis(triphenylphosphine)palladium(0), [bis(diphenylphosphino)ferrocene]dichloropalladium(II), palladium(II) acetate/bis(diphenylphosphino) ferrocene and the like. Generally, about 5 to 10 molar percent of palladium is employed. Suitable weak aqueous bases include, but are not limited to, sodium, potassium, lithium, magnesium, cesium, and calcium carbonate and bicarbonate, and the like. For specific and preferred reaction conditions and reagents for some compounds of the present invention, see Examples 1-6 and 10-27 below.
Alternatively, compounds of formula I may be prepared via a Stille coupling, i.e., coupling an aryl chloride, bromide, or triflate to an aryl stannane. For a review of the Stille coupling, see, e.g., Tetrahedron, 54:276-285, 1998. Typically, the reaction may be performed by dissolving or suspending an aryl triflate of formula II or III, an aryl stannane of formula II or III, a source of palladium(0), and lithium chloride in a suitable solvent such as 1,4-dioxane. Suitable sources of palladium(0) include those listed above for the Suzuki coupling. Typical reaction temperatures range from ambient to the reflux temperature of the mixture. Preferably, the reaction is performed at the reflux temperature of the mixture. Generally, reaction times range from 1 to about 48 hours but, most typically, the reaction is substantially complete after about 18 hours.
Generally, the aryl stannane is employed in a molar excess relative to the aryl triflate. Such excesses typically range from about 1.01 to about 1.6 equivalents. In addition, about 5 to 10 molar percent of palladium is typically employed. For specific and preferred reaction conditions and reagents for some compounds of the present invention, see Examples 7-9 below.
Since the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutical acid addition salts. Since some of the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their pharmaceutical acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature.
The pharmaceutical acid addition salts of the invention are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethylether, tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, benzene, and the like. The salts normally precipitate out of solution within about one hour to about ten days and can be isolated by filtration or other conventional methods.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, ethanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, tartaric acid, benzoic acid, acetic acid, and the like.
The compounds of formula II where A is carbon, D is NH, and E is nitrogen (indazoles) may be prepared from compounds of formula II where A is carbon, D is NH, and E is carbon (indoles) as illustrated in Scheme 2 below where R6 is amino, nitro, chloro, bromo, or hydroxy, and G, J, R2, and R3 are as defined above. 
Compounds of formula IV may be prepared by adding a solution of about 2 to 2.5 equivalents of a periodate, typically sodium periodate in water, to a compound of formula II(a) dissolved in a suitable solvent, typically a mixture of methanol and water. Generally, in order to facilitate dissolution in this methanol/water solvent system and to protect the indole NH from oxidation, a salt of a compound of formula II(a) will be employed, e.g., the hydrochloride, or an acid will be added to the reaction mixture to form a salt while reacting, e.g., methanesulfonic acid. The reaction may be performed at temperatures ranging from 0xc2x0 C. to the reflux temperature of the reaction mixture for from 8 hours to 2 weeks but is usually performed at ambient temperatures. In certain cases, e.g., when R6 is nitro, the deformylation may occur spontaneously during the periodate oxidation step. Thus, the chemistry described in the next paragraph may not be required for all compounds of formula II(a) used in the above reaction.
In cases where a separate step is necessary to remove the formyl group, a compound of formula V may prepared by treating a compound of formula IV with an excess of an appropriate base dissolved in a lower alkanol, typically sodium hydroxide in methanol. This reaction may be performed at temperatures ranging from ambient to the reflux temperature of the mixture for from 1 to 24 hours. Typically, the reaction is performed at about 45xc2x0 C. for about 2 hours.
The indazoles of formula II(b) may now be prepared by treating a compound of formula V, dissolved in a suitable acidic solvent, with a solution of about 1 equivalent of a nitrite, typically sodium nitrite in water, to create an intermediate diazonium salt. Once the diazonium salt is formed, typically in about 15 minutes to 1 hour, it may be converted to the indazole product by adding this mixture to a large excess of sulfur dioxide, typically as a saturated solution in water. The addition of nitrite may be performed at temperatures ranging from xe2x88x9250xc2x0 C. to about ambient temperature but is typically performed at about 0xc2x0 C. The inverse addition of the diazonium salt to the sulfur dioxide solution may also be performed cold as described above but is usually performed at about 3xc2x0 C. Once the additions are complete, the reaction may be run cold for a short time, e.g., from about 15 minutes to 1 hour, but is then allowed to warm to ambient temperature and stir for an additional 12 to 24 hours.
Compounds of formula II other than indazoles (A is carbon, D is NH, and E is nitrogen) may be prepared by methods known to one of ordinary skill in the art. For example, compounds of formula II where A and E are carbon, D is NH, and R2 is C1-C6 alkyl may be prepared as taught in U.S. Pat. No. 5,708,008 (""008), the teachings of which are herein incorporated by reference. All other non-indazole compounds of formula II may also be prepared substantially as described for compounds where D is NH and R4 is C1-C6 alkyl in ""008. These syntheses are illustrated below in Scheme 3 where A, D, R1, R21R3 and R6 are as defined above. 
A compound of formula VI may be condense with a compound of formula VII in the presence of a suitable base to give the corresponding compound of formula II (c). For indoles and azaindoles of formula II(c) (D is NH), the reaction may be performed by adding the respective compounds of formula VI and VII to a mixture of an appropriate base (typically sodium or potassium hydroxide) in a lower alkanol, typically methanol or ethanol. About 1 to about 5 equivalents of a compound of formula VII, relative to the compound of formula VI are generally employed. A range of about 1.3 to 2.3 equivalents is preferred. The reaction is typically performed for about 0.25 to 24 hours.
For benzofuran or benzothiophene compounds of formula II(c) (D is oxygen or sulfur) the reaction may be performed by first reacting a benzofuran or benzothiophene of formula VI where R6 is amino or preferably nitro with bromine in acetic acid. The reaction is typically performed at about 50xc2x0 C. for about 4 hours. After the bromination is substantially complete, the volatiles are then removed under reduced pressure and the residue is subjected to an extractive work-up under basic conditions. The resulting 3-bromobenzothiophene or 3-bromobenzofuran in diethyl ether is then treated with an alkyl lithium, typically n-butyl lithium, in the same solvent, at xe2x88x9278xc2x0 C. to affect a metal-halogen exchange. After stirring at this temperature for about 1 hour, the reaction mixture is treated with an equivalent of an appropriate compound of formula VII. Once the addition of the compound of formula VII is complete, the reaction mixture is stirred at xe2x88x9278xc2x0 C. for an additional 3 to 5 hours. It is critical, when R1 is hydrogen, to maintain the reaction mixture at this temperature to avoid equilibration of the anion to the 2-position of the benzofuran or benzothiophene ring. The reaction mixture is then allowed to warm to xe2x88x9220xc2x0 C. over about 50 minutes. An excess of an appropriate base, preferably sodium or potassium hydroxide, in a lower alkanol, typically methanol or ethanol is then added and the reaction refluxed for 0.25 to 24 hours to provide a benzofuran or benzothiophene compound of formula II(c) where R6 is amino or nitro.
If desired, compounds of formula II(c) may be hydrogenated over a precious metal catalyst to give the corresponding compounds of formula II(d). When R6 is bromo, a catalyst such as sulfided platinum on carbon, platinum oxide, or a mixed catalyst system of sulfided platinum on carbon with platinum oxide may be used to prevent hydrogenolysis of that bromo substituent during the reduction. The hydrogenation solvent may consist of a lower alkanol, such as methanol or ethanol, tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and ethyl acetate. The hydrogenation may be performed at an initial hydrogen pressure of 20 p.s.i. to 80 p.s.i., preferably from 50 p.s.i. to 60 p.s.i., at 0xc2x0 C. to 60xc2x0 C., preferably at ambient temperature to 40xc2x0 C., for 1 hour to 3 days. Additional charges of hydrogen may be required to drive the reaction to completion depending on the specific substrate.
When the hydrogenation is performed with a compound of formula II(c) where R6 is amino or nitro, more vigorous hydrogenation conditions may be used without disrupting the rest of the molecule. For example, a catalyst such as platinum or palladium on carbon may be utilized without substantially effecting deleterious side reactions. Thus, when it is required to employ an intermediate where R6 is amino or nitro, i.e., for the benzofurans and benzothiophenes, such a procedure may be advantageous and preferred.
In general, when R6 is nitro, that nitro group may be reduced to an amine at any convenient point in the syntheses outlined in Schemes 2 and 3 by well known methodology. See, e.g., Larock, xe2x80x9cComprehensive Organic Transformationsxe2x80x9d, pgs. 412-415, VCH Publishers, New York, N.Y., 1989. Additionally, when R6 is nitro in compounds of formula II(c), that nitro group and the double bond may be hydrogenated simultaneously if desired to give a compound of formula II(d) where R6 is amino by many of the methods described by Larock for the nitro group alone. Furthermore, methods for selective reduction of a double bond in the presence of a nitro group are known in the art and one example of that transformation may be found in Preparation 18 below.
When R6 is amino, that amino group may be converted to bromo via the Sandmeyer reaction at any convenient point in the syntheses outlined in Schemes 2 and 3 by procedures taught by M. P. Doyle in J. Org. Chem., 42:2426, 1977. If needed, it is preferred to perform the Sandmeyer reaction after the conversion of a compound of formula II(c) to a compound of formula II(d).
When R6 is hydroxy, that free hydroxy group may have a trifluoromethanesulfonyl group (SO2CF3) installed by standard procedures known in the art at any convenient point in the syntheses outlined in Schemes 2 and 3. For example, a compound of formula II(c) where R6 is hydroxy may be reacted with trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride in the presence of an appropriate base to give a compound of formula II(c) where R6 is OSO2CF3. See Preparation 17 below for a detailed description of such a conversion.
When R6 is bromo or chloro, that bromo or chloro group may be converted to a boronic acid (B(OH)2) at any convenient point in the syntheses outlined in Schemes 2 and 3. For example, this conversion may be performed by executing a metal-halogen exchange as described above on a compound of formula II(b) followed by the addition of a source of borate, e.g., triisopropyl borate. See Preparation 3 below for a detailed description of such a conversion.
Furthermore, when R6 is bromo or chloro, that bromo or chloro group may be converted to a stannane via well known procedures at any convenient point in the syntheses outlined in Schemes 2 and 3. For example, this conversion may be performed by reacting a chloro or bromo compound of formula II(d) with a compound of the formula Sn2(C1-C4 alkyl)6 in a suitable solvent such as 1,4-dioxane to form a compound of formula II(d) where R6 is Sn(C1-C4 alkyl)3. Usually, hexamethylditin or hexabutylditin is employed. See Example 7 below for a detailed description of a similar conversion.
Compounds of formula II(a), II(b), II(c), and II(d) where R6 is chloro, bromo, Sn(C1-C4 alkyl)3, B(OH)2, or OSO2CF3 prepared as described above may be utilized as in Scheme 1.
The compounds of formula VI where A is carbon and D is NH (indoles), may be prepared by methods well known to one of ordinary skill in the art, such as that generally described in U.S. Pat. No. 4,443,451, the teachings of which are hereby incorporated by reference. While these indoles are generally commercially available, their preparations are also described in Robinson, The Fischer Indole Synthesis, Wiley, New York, 1983; Hamel, et al., Journal of Organic Chemistry, 59:6372, 1994; and Russell, et al., Organic Preparations and Procedures International, 17:391, 1985.
The compounds of formula VI where A is nitrogen, D is NH, R1 is hydrogen, and R6 is hydroxy, may be prepared by methods disclosed in Preparations 4-8 and 11 below. Once prepared, the resulting compound of formula VI (5-hydroxy-4-aza-1H-indole) may be condensed with a compound of formula VII by the procedure described above in Scheme 3. Once condensed, a 5-hydroxy-4-aza-1H-indole compound of formula II(c) or II(d) may have its 5-hydroxy group displaced (after the hydroxy group has been activated for displacement, see Preparation 12) by a suitable source of bromide ion such as phosphorous tribromide. Once prepared, the 5-bromo-4-azaindoles may have a C1-C6 alkyl group installed at R1 via standard alkylating procedures provided that the indole NH is protected as described above in Greene. For example, 5-bromo-4-aza-1-triisopropylsilylindole may be treated with a base such as a sodium, lithium, or potassium hydride to generate an anion at the 2-position of the 4-azaindole ring system. The addition of a C1-C6 alkyl chloride, bromide, or iodide to this anionic mixture, followed by removal of the protecting group, affords a compound of formula II(c) II(d) where R1 is C1-C6 alkyl.
Compounds of formula VI where D is oxygen (benzofurans) or sulfur (benzothiophenes) may be prepared by known procedures such as that described in Scheme 4 below where L is oxygen or sulfur and R1 and R6 are as defined above. 
An xcex1-halo-acetaldehyde of formula VIII, optionally protected as the corresponding acetal, may be reacted with an appropriately substituted, commercially available, phenol or thiophenol of formula IX under standard alkylating conditions to provide the corresponding ether or thioether of formula X. This ether or thioether may be converted to a benzofuran or benzothiophene of formula VI(b) by heating a compound of formula X in the presence of an acid, typically polyphosphoric acid or sulfuric acid. When R6 is amino in compounds of formula IX or X, that amino group should be protected with an appropriate amino protecting group as described in Greene. The protecting group may be chosen such that it is hydrolyzed during the cyclization step or, if desired, the unprotected compounds of formula VI(b) where R6 is amino may be prepared in a separate deprotection step if necessary. Furthermore, these amino compounds of formula VI(b) may be converted to the corresponding halo compounds via the Sandmeyer reaction described above.
Compounds of formula VII where R2 and R3 combine, together with the 6 membered ring to which they are attached, to form a 6:5, 6:6, or 6:7 fused bicyclic ring may be prepared from methylvinyl ketone and an appropriate amino-dialkylacetal or -cyclic acetal according to the procedures found in Tet. Let., 24:3281, 1983, and J.C.S. Perk. I, 447, 1986. These acetals are generally commercially available or can be synthesized by well known methods in the art from their corresponding commercially available 4-substituted butanals or 5-substituted pentanals. This chemistry is illustrated in Scheme 5, where m is 3,4, or 5 and R7 and R8 are C1-C4 alkyl or R7 and R8 taken together with the oxygen atoms, to which they are attached, form a 5 or 6 membered cyclic acetal, and n is 0, 1, or 2. 
Compounds of formula VII(a) may be prepared by acid treatment of the addition product of methyl vinyl ketone and a compound of formula XI. A diethylacetal of formula XI is a preferred starting material for this reaction (R7 and R8 are ethyl). The reaction may be performed by first dissolving an appropriate aminoacetal of formula XIII in an suitable solvent, typically diethyl ether at 0xc2x0 C., and then adding approximately 1.7 equivalents of methyl vinyl ketone. Typically the reaction is allowed to stir at 0xc2x0 C. for approximately 2 hours before acidification by addition of, or extraction with, aqueous hydrochloric acid. Usually, the organic layer is removed before heating the aqueous layer to approximately 100xc2x0 C. for 1 hour. The resulting 7-octahydroindolizinone, 2-octahydro-2H-quinolizinone, or 4-(1-azabicyclo[5.4.0]undecan)ones of formula VII(a) may be isolated from the reaction mixture by adjusting the pH of the solution to alkaline and extracting with a water immiscible solvent such as ethyl acetate or dichloromethane.
Compounds of formula VII(a) prepared as described in Scheme 5 are racemic and, if used as described in Schemes 1-4 will produce racemic compounds of the invention. Compounds of the invention that are optically enhanced in one enantiomer may be obtained by resolving the compounds of formula VII(a) before use of these compounds as described in Schemes 3. Methods of resolving enantiomeric compounds of this type are well known in the art. For example, resolution can be achieved by use of chiral chromatography. Furthermore, racemic compounds of formula VII(a) may be converted to their corresponding diastereomeric mixture of salts by reaction with a chiral acid such as (+) or (xe2x88x92) tartaric acid. The diastereomers may then be separated and purified by recrystallization. Once separated, the salts may each be converted back to the chiral free base compounds of formula VII(a) by reacting the salts with an aqueous base, such as sodium hydroxide, then extracting the mixture with a common organic solvent. The optical purity in resolved compounds of formula VII(a) is maintained while undergoing the chemistry described in this application to afford optically pure compounds of the invention. As an alternative, when advantageous, the resolution techniques just discussed may be performed at any convenient point in the syntheses described in Schemes 1-3.
The xcex1-halo aldehydes, or corresponding acetals of formula VIII are either commercially available or may be prepared from the corresponding acids or acid halides by methods well known to one of ordinary skill in the art. This chemistry is reviewed by Larock, xe2x80x9cComprehensive Organic Transformations,xe2x80x9d pages 378-379, VCH Publishers, New York, 1989. Compounds of formula III, VI, VII, VIII, IX, and XI are known in the art and, to the extent not commercially available, are readily synthesized by standard procedures commonly employed in the art such as those described herein.
The optimal time for performing the reactions of Schemes 1-5 may be determined by monitoring the progress of the reaction via conventional chromatographic techniques, e.g., thin layer chromatography and high performance liquid chromatography. Furthermore, it is usually preferred to conduct the reactions of Scheme 1-5 under an inert atmosphere, such as, for example, argon, or, particularly, nitrogen. Choice of solvent is generally not critical so long as the solvent employed is inert to the ongoing reaction and sufficiently solubilizes the reactants to effect the desired reaction. The intermediate compounds of this invention are preferably purified before their use in subsequent reactions. The intermediates and final products may be purified when, if in the course of their formation, they crystallize out of the reaction solution. In such a situation, the precipitate may be collected by filtration and washed with an appropriate solvent. Certain impurities may be removed from the organic reaction mixture by aqueous acidic or basic extraction followed by removal of the solvent by extraction, evaporation, or decantation. The intermediates and final products of formula I may be further purified, if desired by common techniques such as recrystallization or chromatography over solid supports such as silica gel or alumina.